Glucagon-Like Peptide-1 Receptor Agonist Treatment in Adult, Obesity-Related, Symptomatic Asthma

项目摘要 肥胖对哮喘明显有害，但我们缺乏治疗独特的肥胖哮喘表型的工具。 共病肥胖影响>40%的成人哮喘患者1，并增加哮喘的严重程度、症状和 急性加重，同时降低常规治疗的疗效。2 -5我们的长期目标是 开发新的治疗肥胖型哮喘的气道炎症的方法。我们的总体目标是， 是转化我们的临床前和初步临床研究结果的下一步，是确定 胰高血糖素样肽-1受体激动剂（GLP-1 RA）对哮喘控制以及气道和脂肪炎症的作用 肥胖性哮喘的成年人。我们的中心假设是GLP-1 RA可改善哮喘控制， 肥胖性哮喘中由于直接作用于呼吸道而引起的气道炎症。以生成证据- 支持GLP-1 RA治疗肥胖性哮喘表型和检测的确定性III期临床试验的概念数据 我们的中心假设，我们提出了以下具体目标：1）确定GLP-1 RA对 哮喘控制和评估肥胖性哮喘的耐受性，2）确定GLP-1对组织的特异性影响， 1 RA对肥胖性哮喘气道炎症和脂肪组织炎症的影响。在一项为期12周的双盲、随机、 一项在肥胖相关、症状性成人受试者中评价semaglutide口服制剂7 mg每日一次的安慰剂对照试验 在无DMII的哮喘中，我们将检验Semaglutide改善哮喘控制（目的1a）的假设， 耐受性（目标1b）和减少2型和非2型气道炎症，与体重减轻无关（目标2）。 主要临床结局为ACQ-7较基线的变化。主要的机械结果将是 血清骨膜蛋白较基线的变化。因为胰岛素抵抗在肥胖和基线血液中是可变的 嗜酸性粒细胞计数通常预测对哮喘治疗剂的反应，这些标志物将用于 预先指定的亚组分析。基线时皮下腹部脂肪和呼吸道样本 将使用RNA测序对治疗5周和12周进行比较，以检验GLP-1 RA 减少炎症以恢复呼吸道的稳态，这与脂肪组织的变化相反， 肥胖性哮喘该提案有助于收集必要的临床，机制和耐受性 为GLP-1 RA治疗哮喘的确定性III期临床试验设计提供信息的数据。因此，它支持 新型哮喘治疗类别的快速发展，代表了哮喘治疗方法的范式转变 通过靶向调节上游代谢途径的哮喘治疗干预 在多个器官系统中的炎症，可能是疾病修饰，并最终是糖皮质激素节省。

Project Summary Obesity is clearly detrimental in asthma, yet we lack tools to treat the unique obese asthma phenotype. Comorbid obesity impacts >40% of adult asthmatics1 and increases asthma severity, symptoms and exacerbations while simultaneously reducing the efficacy of conventional therapies.2-5 Our long-term goal is to develop novel treatments for airway inflammation in the obese asthma phenotype. Our overall objective, which is the next step in translating our preclinical and preliminary clinical findings, is to determine the impact of glucagon-like peptide-1 receptor agonists (GLP-1RA) on asthma control and airway and adipose inflammation in adults with obese asthma. Our central hypothesis is that GLP-1RA improve asthma control and reduce airway inflammation due to direct effects on the respiratory tract in obese asthma. To generate the proof-of- concept data to support definitive phase 3 clinical trials of GLP-1RA in the obese asthma phenotype and test our central hypothesis, we propose the following specific aims: 1) Determine the efficacy of GLP-1RA on asthma control and assess tolerability in obese asthma and 2) Determine the tissue-specific impact of GLP- 1RA on inflammation in the airway and adipose in obese asthma. In a 12-week double-blind, randomized, placebo-controlled trial of oral semaglutide 7 mg once daily in adult subjects with obesity-related, symptomatic asthma without DMII, we will test the hypotheses that semaglutide improves asthma control (aim 1a), is tolerated (aim 1b) and reduces type-2 and non-type 2 airway inflammation independent of weight loss (aim 2). The primary clinical outcome will be change from baseline in ACQ-7. The primary mechanistic outcome will be change from baseline in serum periostin. Because insulin resistance is variable in obesity and baseline blood eosinophil counts are often predictive of response to asthma therapeutics, these markers will be used for prespecified subgroup analyses. Subcutaneous abdominal adipose and respiratory tract samples at baseline and 5 and 12 weeks of therapy will be compared using RNA sequencing to test the hypothesis that GLP-1RA reduce inflammation to restore homeostasis in the respiratory tract opposite to changes in adipose tissue in obese asthma. This proposal facilitates the collection of the necessary clinical, mechanistic, and tolerability data to inform the design of a definitive phase III clinical trial of a GLP-1RA in asthma. It thereby supports the rapid development of a novel therapeutic class for asthma and represents a paradigm shift in the approach to therapeutic intervention in asthma through the targeting of a metabolic pathway which regulates upstream inflammation across multiple organ systems, may be disease modifying, and ultimately glucocorticoid sparing.